Tightly packed chromatin is like a closed book that keeps valuable information tucked away. This includes epigenetic information that can be read by DNA-repair complexes, which can use the information to locate DNA lesions, like those that accumulate in fast-dividing cancer cells. The closed book, however, flips open during cell division, revealing epigenetic secrets that could be exploited by anticancer therapies.
The possibility of interfering with cancer-preserving repair mechanisms is part of what motivates the work of scientists at the University of Copenhagen’s Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics. These scientists, led by Professor Anja Groth, report that they have found a histone-binding protein that has very particular tastes in reading: it is sensitive to post-replicative chromatin.
“We have shown how a cellular DNA repair protein is directed to lesions in DNA via modifications on histone proteins that are bound tightly to DNA,” explained Prof Groth. “Cancer cells divide rapidly and experience a high load of DNA damage—without efficient repair systems these cells will die. Accordingly, cancer cells are highly dependent upon DNA repair mechanisms, and this new molecular mechanism we have found constitutes an attractive target for cancer therapy.”
Details about the newly discovered mechanism appeared June 22 in the journal Nature, in an article entitled, “H4K20me0 Marks Post-Replicative Chromatin and Recruits the TONSL–MMS22L DNA Repair Complex.” The article maintains that the mechanism offers a “new angle to understand DNA repair with the potential for targeted cancer therapy.”
In collaboration with Dinshaw Patel, Ph.D., at Memorial Sloan-Kettering Cancer Center in New York, the research group from BRIC has obtained a detailed crystal structure of the TONSL (“tonsoku-like”) protein bound to the histone protein, which they show directs TONSL to DNA lesions. This structure tells researchers how the protein works and gives them the opportunity to design a molecule that can bind to TONSL and prevent it from locating the DNA damages. Such an inhibitor molecule may be used in the treatment of cancer because blocking of TONSL function could promote cancer cells to accumulate DNA damage and eventually die.
“We identify the TONSL ankyrin repeat domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until the G2/M phase of the cell cycle,” wrote the authors of the Nature article. “Accordingly, TONSL–MMS22L binds new histones H3–H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M.
“H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability, and resistance to replication stress.”
The scientists at BRIC assert that their discovery provides a new foundation for understanding how chromatin, the structure that organizes DNA in the nucleus, directs DNA repair processes within our cells. “We have discovered that the TONSL molecule recognizes a special chromatin signature which arises when the DNA is duplicated during cell division,” emphasized Giulia Saredi, a Ph.D. student at BRIC. “TONSL is able to read this signature to boost the repair of damages in our DNA.”
The BRIC research team has now put together a team of experts in medicinal chemistry and rational drug design to develop small molecule inhibitors. “This discovery shows, once again, that society's investment in understanding basic biological processes is vital to open new avenues that can be explored for disease treatment,” concluded Prof. Groth. “The possibility of exploiting our basic research findings for advancing cancer treatment in the future is an important driving force in our work.”